Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 21, 2024; 30(7): 728-741
Published online Feb 21, 2024. doi: 10.3748/wjg.v30.i7.728
Milk fat globule epidermal growth factor 8 alleviates liver injury in severe acute pancreatitis by restoring autophagy flux and inhibiting ferroptosis in hepatocytes
Qing Cui, Hang-Cheng Liu, Wu-Ming Liu, Feng Ma, Yi Lv, Jian-Cang Ma, Rong-Qian Wu, Yi-Fan Ren
Qing Cui, Feng Ma, Department of Cardiology, Xi’an Central Hospital Affiliated to Xi’an Jiaotong University, Xi’an 710003, Shaanxi Province, China
Hang-Cheng Liu, Yi-Fan Ren, Department of General Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
Wu-Ming Liu, Yi Lv, Rong-Qian Wu, Yi-Fan Ren, National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
Wu-Ming Liu, Yi Lv, Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
Jian-Cang Ma, Department of Vascular Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
Co-first authors: Qing Cui and Hang-Cheng Liu.
Author contributions: Cui Q, Liu HC, and Liu WM acquired and analyzed the data, wrote the paper; Ma F, Lv Y, Ma JC, and Wu RQ interpreted the data; Lv Y, Wu RQ, and Ren YF revised the paper; Ren YF designed and supervised the study; and all authors approved the final version of the article.
Supported by the National Natural Science Foundation of China, No. 82100685; the Scientific Research Fund of Xi’an Health Commission, No. 2021yb08; Scientific Research Fund of Xi’an Central Hospital, No. 2022QN07; and Innovation Capability Support Plan of Xi’an Science and Technology Bureau, No. 23YXYJ0097.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of the Xi’an Jiaotong University.
Institutional animal care and use committee statement: This study was reviewed and approved by the Health Science Center of the Xi’an Jiaotong University Approval for Research Involving Animals (No. XJTUAE2023-2254).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: Data used to support the findings of this study are available from the corresponding author upon request.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Yi-Fan Ren, MD, PhD, Assistant Professor, Surgeon, Department of General Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 West Fifth Road, Xi’an 710004, Shaanxi Province, China. 871396704@qq.com
Received: October 21, 2023
Peer-review started: October 21, 2023
First decision: December 5, 2023
Revised: December 18, 2023
Accepted: January 15, 2024
Article in press: January 15, 2024
Published online: February 21, 2024
Processing time: 123 Days and 3.1 Hours
Abstract
BACKGROUND

Liver injury is common in severe acute pancreatitis (SAP). Excessive autophagy often leads to an imbalance of homeostasis in hepatocytes, which induces lipid peroxidation and mitochondrial iron deposition and ultimately leads to ferroptosis. Our previous study found that milk fat globule epidermal growth factor 8 (MFG-E8) alleviates acinar cell damage during SAP via binding to αvβ3/5 integrins. MFG-E8 also seems to mitigate pancreatic fibrosis via inhibiting chaperone-mediated autophagy.

AIM

To speculate whether MFG-E8 could also alleviate SAP induced liver injury by restoring the abnormal autophagy flux.

METHODS

SAP was induced in mice by 2 hly intraperitoneal injections of 4.0 g/kg L-arginine or 7 hly injections of 50 μg/kg cerulein plus lipopolysaccharide. mfge8-knockout mice were used to study the effect of MFG-E8 deficiency on SAP-induced liver injury. Cilengitide, a specific αvβ3/5 integrin inhibitor, was used to investigate the possible mechanism of MFG-E8.

RESULTS

The results showed that MFG-E8 deficiency aggravated SAP-induced liver injury in mice, enhanced autophagy flux in hepatocyte, and worsened the degree of ferroptosis. Exogenous MFG-E8 reduced SAP-induced liver injury in a dose-dependent manner. Mechanistically, MFG-E8 mitigated excessive autophagy and inhibited ferroptosis in liver cells. Cilengitide abolished MFG-E8’s beneficial effects in SAP-induced liver injury.

CONCLUSION

MFG-E8 acts as an endogenous protective mediator in SAP-induced liver injury. MFG-E8 alleviates the excessive autophagy and inhibits ferroptosis in hepatocytes by binding to integrin αVβ3/5.

Keywords: Autophagy flux, Ferroptosis, Liver injury, Milk fat globule epidermal growth factor 8, αvβ3/5 integrins, Acute pancreatitis

Core Tip: Serum milk fat globule epidermal growth factor 8 (MFG-E8) concentration is negatively correlated with inflammatory severity in acute pancreatitis (AP) patients. Deficiency of MFG-E8 would aggravate the hepatic inflammatory response, and exacerbates the imbalance of liver autophagy flux caused by AP. Eventually leading to ferroptosis. Recombinant MFG-E8 administration restored autophagy flux, reduced ferroptosis and alleviated liver injury in AP in a dose-dependent manner. MFG-E8 alleviates the excessive autophagy and inhibits ferroptosis in hepatocytes possibly by binding to integrin αVβ3/5.